• dystrophin-glycoprotein complex
• limb-girdle muscular dystrophy
• sarcoglycanopathies
• genotype-phenotype correlations

The limb-girdle muscular dystrophies (LGMDs) are genetically determined progressive disorders clinically defined by the primary involvement of the pelvic and shoulder girdle musculature.¹ Among autosomal recessive LGMDs (LGMD 2), sarcoglycanopathies (LGMD 2C-2F) represent a subgroup caused by mutations in one of the genes that encode γ-, α-, β-, and δ-sarcoglycans (SGs), respectively.^2–6 The SGs are transmembrane glycoproteins which, together with sarcospan, dystrophin, dystroglycans, syntrophins, and α-dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC).^7–10 In addition to the four SGs that comprise the SG-sarcospan subcomplex of the DGC in striated muscle,¹¹ a fifth SG, named ε-SG, is expressed in a wide variety of tissues.^12,13 In smooth muscle, ε-SG replaces α-SG as an integral component of a unique SG-sarcospan complex composed of ε-, β-, γ- and δ-SGs and sarcospan.¹⁴ Interestingly, it has been shown that mutations in ε-SG cause myoclonus-dystonia syndrome, an autosomal dominant non-degenerative central nervous system disorder.¹⁵

It is well recognised that the DGC acts as a linker between the cytoskeleton of the muscle cell and the extracellular matrix, providing mechanical support to the plasma membrane during myofibre contraction.^9,16,17 Besides this structural function, there is now increasing evidence that the DGC might play a role in cellular communication, as highlighted by its interaction with signalling molecules such as calmodulin, nitric oxide synthase, and Grb2.^10,17 So far, 41, 20, 10, and six distinct pathogenic mutations have been found in the α- (LGMD 2D), β- (LGMD 2E), γ- (LGMD 2C), and δ-SG (LGMD 2F) genes, respectively (Leiden Muscular Dystrophy pages, www.dmd.nl). Severe clinical Duchenne-like presentations tend to be more common among these patients, with onset occurring early in childhood and confinement to a wheelchair before the age of 16^18–23; however, milder courses have also been described …